Heart Disease, Artery Damage and PCBs

Upcoming Heart Disease Research
on PCB exposure and Cardiovascular Disease

(For 60 studies already completed, see Heart Table of Contents)

HENNIG B. SUPERFUND CHEMICALS AND ENDOTHELIAL CELL DYSFUNCTION. Crisp Data Base National Institutes of Health. Author Address: UNIVERSITY OF KENTUCKY MED CTR, 306 HEALTH SCIENCES RES BLDG, LEXINGTON KY 40536-0305

PCBs have been implicated in the atherosclerotic disease process (heart disease)
PCBs may cause atherosclerotic disease through one or more of these mechanisms:

alteration in lipid profile and lipid metabolism
cytochrome P-450 1A1 induction
increased oxidative stress
DNA adduct formation and oxidative DNA damage
alteration of calcium metabolism

Polyhalogenated aromatic hydrocarbons (e.g. PCBs) and polycyclic aromatic hydrocarbons (e.g., BP) have been implicated in the atherosclerotic disease process. Even though mechanisms of the atherogenic potential of these environmental contaminants are not known, critical events of cell dysfunction may occur at the endothelial cell level. The vascular endothelium 'communicates' with blood-borne cells and abluminal tissues and acts as a barrier to the movement of plasma components (e.g., cholesterol-rich lipoproteins) from the blood to the arterial wall. Cell injury, or any event which disrupts endothelial integrity and thus endothelia permeability properties, may be involved in the early events leading to atherosclerotic lesion formation. We propose that aromatic hydrocarbons are atherogenic by causing cell dysfunction and a subsequent disruption of endothelial barrier function. We hypothesize that these events are mediated by 1) alteration in lipid profile and lipid metabolism, 2) cytochrome P-450 1A1 induction, 3) increased oxidative stress, 4) DNA adduct formation and oxidative DNA damage, and 5) alteration of calcium metabolism. Thus, the extent of the movement of atherogenic lipoprotein remnants across and into the arterial wall may be directly correlated to the severity of endothelial cell barrier function disruption. We also hypothesize that diet-derived fats, i.e., fatty acids differing in carbon length and degree of unsaturation, can greatly alter the cellular lipid and oxidant/antioxidant environment and thus influence the aromatic hydrocarbon-mediated cell dysfunction. Furthermore, this research will explore mechanisms by which certain nutrients or chemicals having antioxidant or membrane stabilizing properties, may protect the endothelium from aromatic hydrocarbon-induced cell injury. Porcine- and human-derived endothelial cells will be cultured and used in the proposed research. First, a series of studies will be conducted to determine mechanisms of aromatic hydrocarbon-mediated endothelial cell dysfunction. In the second phase, the interactive events of certain lipids and aromatic hydrocarbons on endothelial cell metabolism will be explored. During the third phase, a series of studies will be undertaken to determine the mechanisms by which selected nutritional interventions in culture may protect agonist cell injury under the conditions cited above. Results of the proposed studies should identify mechanisms of Superfund Chemical-mediated endothelial cell dysfunction and their implication in atherosclerosis.

HOORN CM. ENVIRONMENTAL TOXICANTS AND ENDOTHELIAL FUNCTION. Crisp Data Base National Institutes Of Health. Author Address: WESTERN MICHIGAN UNIVERSITY, KALAMAZOO, MI 49008

PCBs may promote atherosclerosis (heart disease) through alterations in endothelial cell structure and function

Atherosclerosis is a degenerative process affecting large- and medium- sized arteries and is characterized by fibrotic, lipid-containing plaques. This condition underlies most of today's prevalent cardiovascular diseases and is thus a leading contributor to death in the United States and other "westernized" nations. Endothelial cell injury/dysfunction has been identified very early in the development of atherosclerotic lesions. The response-to-injury hypothesis acknowledges that injured or activated endothelial cells may themselves participate in the development of atherosclerosis, and a number of the identified risk factors thought to contribute to this disease, including hypertension or hypercholesterolemia, may act in part by damaging endothelial cells or exacerbating the unavoidable effects of aging or shear stress on this vital cell population. In the proposed studies, a cultured endothelial cell system will be used to test the hypothesis that exposure to low concentrations of certain environmental chemicals results in alterations in endothelial cell structure and function that may contribute to the initiation of atherosclerotic lesions. Some evidence exists suggesting that chemicals such as dimethylbenzanthracene, benzo(a)pyrene, cadmium, arsenic, carbon disulfide, and the polychlorinated biphenyl mixture, Aroclor 1242, are vascular toxicants. These chemicals will be examined for their ability to: l.) cause overt endothelial cell injury, cell proliferation and changes in monolayer binding of labeled low-density lipoprotein and permeability to albumin, 2.) contribute to the oxidation of low-density lipoprotein by enhancing the generation of reactive oxygen species (e.g., superoxide anion) by endothelium, and 3.) enhance the binding of monocytes to endothelial cells. These initial studies should provide a number of directions for future investigations, both in vitro and in vivo, including determination of the mechanisms underlying the observed effects. The vascular toxicity of many of these chemicals has not been investigated in a systematic manner in relevant species, and the effects of chronic, low-level exposure to these and other environmental contaminants on endothelial cell function are unknown. In general, vascular toxicology and the contribution of toxicants to the development of chronic vascular disease is an area of research that has received little attention. Identification of compounds that contribute to this prevalent and potentially lethal condition could be helpful in setting guidelines for safe exposure limits and may lead to a better understanding of the etiology and development of atherosclerosis and other vascular diseases.

MATSUMURA F. BIOCHEMICAL CAUSES FOR HYPERTRIGLYCERIDEMIA. Crisp Data Base National Institutes Of Health Author Address: UNIVERSITY OF CALIFORNIA, ITEH, DAVIS, CA 95616

PCBs are known to cause acute and chronic hyperlipidemia
dioxins cause early atherosclerosis and reduction in the contraction force of the heart atrial muscles (certain PCBs are dioxin-like)

Dioxin-type chemicals including PCBs are known tocause acute and chronic hyperlipidemia accompanied with the loss of body fat in several experimental animal species. Not only that most of these chemicals are hardly metabolized by detoxification enzymes and coupled with their extreme lipophilicity, concentrate in the adipose tissues where they remain for a long time period, often for the entire lifespan of the animal. We have previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes significant reduction in the lipoprotein lipase (LPL) levels in the adipose tissue of guinea pigs and rabbits. Such an observation helps to explain why in these species the most predominant toxic expression of TCDD is hypertriglyceridemia. We have also found a number of evidence that TCDD causes early atherosclerosis and reduction in the contraction force of the heart atrial muscles. Since lipid metabolism is known to play a vital role in nutritional homeostasis, and since these dioxin-type chemicals are now commonly found in adipose tissues of various animals including humans, we propose to study this further. In more specific terms, we plan to study (1) acute and chronic effects of TCDD on adipose LPL, synthesis and the ability of the affected adipocytes to respond to high glucose to produce LPL, (2) since TCDD causes a drastic increase in protein kinase activities in the adipose, as in the case of other tissues, characterize the nature of protein kinases, and identify the major substrate proteins for those TCDD affected protein kinases, including insulin and B-adrenergic receptor, (3) establish an in vitro adipocytes system which adequately reproduces the effect of TCDD particularly that on LPL synthesis processes, and (4) by using the knowledge gained by the above studies develop a reliable biomarker to indicate the extent of exposure to hardly metabolizable congeners of PCBs, dioxins and PCDFs. The markers proposed for study are levels of mRNA for LPL, 3H-TCDD binding to the adipocyte nuclear receptor, protein kinase C, protein tyrosine kinase (using antibodies against phosphotyrosine), pp6Olsrc (using specific antibody), and (125)I-insulin binding to its receptor.

ROBERTSON LW. SUPERFUND CHEMICALS--TRANSPORT METABOLISM AND TOXICITY. Crisp Data Base National Institutes Of Health. Author Address: UNIVERSITY OF KENTUCKY MED CTR, 306 HEALTH SCIENCES RES BLDG, LEXINGTON KY 40536-0305

PCBs may be atherogenic (cause heart disease) by causing a breakdown in endothelial barrier function.

This program is focusing on issues of detection, metabolism, and toxicity of polychlorinated biphenyls (PCBs). The research will provide a more compete picture of the risks PCBs have for humans, from their environmental detection and metabolism through their effects on hepatic initiation and promotion as well as their involvement in other toxic phenomena. The program consists of four projects (3 biomedical and one non-biomedical) and synthesis and administrative costs. One of the biomedical projects is investigating specific mechanisms of activation of PCBs to toxic metabolites within the cell and organism. Researchers are examining issues of metabolic activation of PCBs to electrophilic, genotoxic species in vivo. The target of these activated metabolites would be cellular nucleophilic sites in protein, RNA, and DNA. Metabolism of PCBs may also give rise to reactive oxygen species. Their presence and reaction products will also be determined in vivo models. The other two biomedical projects are investigating the mechanism of toxic effects of PCBs in specific cell types. In one project, researchers are attempting to determine the mechanisms(s) of toxicity of congeneric PCBs in endothelial cells in culture. The hypothesis being tested is that PCBs are atherogenic by causing a breakdown in endothelial barrier function. This results in the enhanced transfer of plaque-forming substances from the vessel lumen into the arterial wall. This project will examine the specific types of lesions caused by PCBs in monolayers of endothelial cells. The other project is focusing on mechanisms of hepatic tumor promotion by PCBs. Using the rat liver model, researchers are examining: if PCBs induce changes in cellular proliferation or oxidative DNA damage, if PCBs inhibit apoptosis, and the mechanism of any effects. In the non-biomedical project, researchers are developing optical sensing systems for the detection of PCBs. Investigators are first constructing plasmids that contain the bacterial bph operon, mammalian dioxin-responsive enhancers, and the luciferase gene, which is responsible for the generation of luminescence. Next cellular systems that will bioluminesce in the presence of PCBs after insertion of the engineered plasmids will be prepared. Finally, biosensors will be developed using these systems. The knowledge of the location and concentration of PCBs will allow a determination of the toxic potential at any given site. These projects are supported by two cores. The synthesis core project provides all the congeneric PCBs required by the research projects. The administrative core coordinates the research efforts through a monthly meeting of faculty, students and research staff, where new findings will be discussed and ideas and concepts tested. A regular seminar open to the public will be established to address environmental issues. This Program will provide for training of several pre- and postdoctoral students.

Studies Without Abstracts

AKAGI K, MURAI K, SHIKATA T. LABORATORY EXAMINATION IN PCBS POISONING PATIENTS WITH SPECIAL REFERENCE TO LIPOPROTEIN. FUKUOKA ACTA MED. 1981, 72(4) 245-248 (JPN). EIS: Epidemiology Information System

Black H. Vitamin E vs. PCBs. Environ Health Perspect 2000 Jan;108(1):A16

BORLAKOGLU JT, WELCH VA. XENOBIOTIC-INDUCED ABERRATIONS OF LIPID METABOLISM. Source: CHOW, C. K. (ED.). FOOD SCIENCE AND TECHNOLOGY (NEW YORK), VOL. 53. FATTY ACIDS IN FOODS AND THEIR HEALTH IMPLICATIONS. XIII+890P. MARCEL DEKKER, INC.: NEW YORK, NEW YORK, USA; BASEL, SWITZERLAND. ILLUS. ISBN 0-8247-8622-X.; 0 (0). 1992. 613-630. HUMAN FATTY LIVER SYNDROME POLYCHLORINATED BIPHENYLS LIPOPROTEINS TOTAL PLASMA PROTEIN FRACTIONS CELLULAR INTAKE HEPATIC DRUG METABOLISM

GOTO M, HIGUCHI K. THE SYMPTOMATOLOGY OF YUSHO (CHLOROBIPHENYLS POISONING) IN DERMATOLOGY. FUKUOKA ACTA MED. 1969, 60(6) 409-431 (JPN) EIS: Epidemiology Information System Includes keyword: Cholesterol

Hirayama C, Okumura M, Nagai J, Masuda Y. Hypobilirubinemia in patients with polychlorinated biphenyls poisoning. Clin Chim Acta 1974 Aug 30;55(1):97-100 (Keyword: triglycerides)

HOLA N, REZNICEK J. GENETIC RISK OF OCCUPATIONAL EXPOSURE TO INCREASED CONCENTRATIONS OF POLYCHLORINATED BIPHENYLS. PRAC LEK; 37 (10). 1985 (RECD. 1986). 386-391. Keywords: HUMAN OCCUPATIONAL HEALTH CYTOGENETIC ANALYSIS PERIPHERAL LYMPHOCYTE BLOOD LIPOPROTEIN CHOLESTEROL

MARKS GS. THE 1986 UPJOHN AWARD LECTURE INTERACTION OF CHEMICALS WITH HEMOPROTEINS IMPLICATIONS FOR THE MECHANISM OF ACTION OF PORPHYRINOGENIC DRUGS AND NITROGLYCERIN. CAN J PHYSIOL PHARMACOL; 65 (6). 1987. 1111-1119. Keywords: HUMAN CHICK EMBRYO LIVER CELL CARDIOVASCULAR-DRUG 3 5 DIETHOXYCARBONYL-1 4-DIHYDRO-2 4 6-TRIMETHYLPYRIDINE POLYCHLORINATED BIPHENYLS 3-2-2 4 6 TRIMETHYLPHENYLTHIOETHYL-4-METHYLSYDNONE TOXICOLOGY FERROCHELATASE UROPORPHYRINOGEN DECARBOXYLASE GUANYLATE CYCLASE CYTOCHROME P-450 PHARMACOKINETICS VASODILATION PORPHYRIA

MASCHEWSKY W. DO WORKPLACE CHEMICALS HARM THE HEART? SOZ- PRAEVENTIVMED; 38 (2). 1993. 71-76. Keywords: HUMAN CARBON DISULFIDE NITRATE ESTER CARBON MONOXIDE ORGANIC SOLVENTS METALS PESTICIDES VINYLCHLORIDE POLYCHLORINATED BIPHENYLS CARDIOVASCULAR TOXICITY

MAXIM LD, HARRINGTON L. A REVIEW OF THE FOOD AND DRUG ADMINISTRATION RISK ANALYSIS FOR POLYCHLORINATED BIPHENYLS IN FISH. REGUL. TOXICOL. PHARMACOL. 1984, 4() 192-219 EIS: Epidemiology Information System. Includes keyword: HYPERTENSION

NAGAI J, FURUKAWA M, YAE Y, IKEDA Y. CLINICO-CHEMICAL INVESTIGATION OF CHLOROBIPHENYLS+ POISONING--ESPECIALLY ON THE SERUM LIPID ANALYSIS OF THE PATIENTS. Source: FUKUOKA ACTA MED. 1969, 60(6) 475-483 (JPN) EIS: Epidemiology Information System

OKUMURA M, MASUDA Y, NAKAMUTA S. CORRELATION BETWEEN BLOOD PCB AND SERUM TRIGLYCERIDE LEVELS IN PATIENTS WITH PCB POISONING. FUKUOKA ACTA MED. 1974, 65(1) 84-87 (JPN) EIS: Epidemiology Information System

OKUMURA M, YAMANAKA M, NAKAMUTA S, UZAWA H. CONSECUTIVE SIX YEAR FOLLOW-UP STUDY ON SERUM TRIGLYCERIDE LEVELS IN PATIENTS WITH PCB POISONING. FUKUOKA ACTA MED. 1975, 66(10) 620-623 (JPN) EIS: Epidemiology Information System

OKUMURA M, YAMANAKA M, NAKAMUTA S. TEN YEAR FOLLOW-UP STUDY ON SERUM TRIGLYCERIDE LEVELS IN 24 PATIENTS WITH PCB POISONING. FUKUOKA ACTA MED. 1979, 70(4) 208-210 (JPN) EIS: Epidemiology Information System

Rosenman KD. Environmental causes of congenital heart abnormalities. Source: Cardiac Problems in Pregnancy 1988;:603-7 Includes keyword: polychlorinated biphenyls

Sak M, Ahlers I. Hypertriglyceridemia as a risk factor in exposition of people to chlorinated diphenyls (author's transl). Cesk Dermatol 1979 Apr;54(2):61-5

UZAWA H, ITO Y, NOTOMI A, KATSUKI S. HYPERGLYCERIDEMIA RESULTING FROM INTAKE OF RICE OIL CONTAMINATED WITH CHLORINATED BIPHENYLS Source: FUKUOKA ACTA MED. 1969, 60(6) 449-454 (JPN) EIS: Epidemiology Information System

UZAWA H, ITO Y, NOTOMI A, HORI S, IKEURA Y, KATSUKI S. CLINICAL AND EXPERIMENTAL STUDIES ON THE HYPERGLYCERIDEMIA INDUCED BY ORAL INGESTION OF CHLORINATED BIPHENYLS. FUKUOKA ACTA MED. 1971, 62(1) 66-73 (JPN) EIS: Epidemiology Information System

UZAWA H, NOTOMI A, NAKAMUTA S, IKEURA Y. CONSECUTIVE THREE YEAR FOLLOW UP STUDY OF SERUM TRIGLYCERIDE CONCENTRATIONS OF 82 SUBJECTS WITH PCB POISONING. FUKUOKA ACTA MED. 1972, 63(10) 401-404 (JPN) EIS: Epidemiology Information System

Wyngaarden JB. From the National Institutes of Health. JAMA 1989 Jun 9;261(22):3214 Medical Subject Headings: Aged, Cardiovascular Diseases/*ETIOLOGY, Female, Hepatic Encephalopathy/DRUG THERAPY, Hepatic Encephalopathy/ETIOLOGY, Human, Infant, Male, Polychlorinated Biphenyls/ADVERSE EFFECTS, Pregnancy, Prenatal Exposure Delayed Effects, Protons, Skull Neoplasms/RADIOTHERAPY.

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